P-hydroxy phenone derivatives and drugs containing these

ABSTRACT

P-hydroxy phenone derivatives of the formula 1 ##STR1## where X is ##STR2## where R 1  =F, Cl, Br or trifluoromethyl or a heteroaryl of the structure ##STR3## with R 2  =C 1  -C 4  - alkyl, 
     Y is a bridging member of the formula --CH═CH--, --CH 2  CH 2  -- or --CH 2  --, 
     n is one of the numbers 2, 3 or 4 and 
     Z is an amino group of the formula --NR 2  R 3  or N--pyrrolidyl or N-piperidyl, where R 2  and R 3  are, independently of one another, C 1  -C 4  -alkyl, as well as the physiologically tolerated salts thereof, are used for preparing antiarrhythmic drugs.

This is a division of application Ser. No. 07/379,357, filed on July 13,1989, now U.S. Pat. No. 4,980,361.

The present invention relates to p-hydroxy phenone derivatives, to drugscontaining them, and to the use thereof for the preparation ofantiarrhythmics of Vaughan-Williams class III.

Antiarrhythmics can be classified according to Vaughan-Williams into 4groups, as follows:

I. sodium antagonists,

II. adrenergic β-receptor blockers,

III. potassium channel inhibitors,

IV. calcium antagonists.

Antiarrhythmics of class III often exhibit the therapeutic advantage ofacting against arrhythmias which are otherwise resistant to therapy,especially reentry arrhythmias. This has been reported both foramiodarone (Circulation 68 (1) (1983), 88-94) and for D-sotalol (Am.Heart J. 109 (1985), 949-958; J. Clin. Pharmacol. 27 (9) (1987), 708).

p-Hydroxy phenones have been reported to have a variety of physiologicalactions: spasmolytics (DE 2,616,484, DE 1,174,311, Arch. Pharm. 1966,299), anti-ulcer agents (JP-A2 52/078-858, JP-A2 52/078-856, JP-A251/100-050), amebicides (FR 5003 M); vaso-dilators (JP-B4 27177/65, GB1,022,648, U.S. Pat. No. 3,407,233, DE 2,062,129, JP-B4 40/06903, JP-B440/06904, JP-B4 74/021125); Ca antagonists (EP 201,400; EP 209,435).

By contrast, the p-hydroxy phenone derivatives claimed in the presentinvention represent, surprisingly, antiarrhythmics of class III.

The present invention relates to p-hydroxy phenone derivatives of theformula I ##STR4## where X is ##STR5## where R¹ =F, Cl, Br ortrifluoromethyl or a heteroaryl of the structure ##STR6## with R² =C₁-C₄ -alkyl,

Y is a bridging member of the formula --CH═CH--, --CH₂ CH₂ -- or --CH₂--,

n is one of the numbers 2, 3 or 4 and

Z is an amino group of the formula --NR² R³ or N-pyrrolidyl orN-piperidyl, where R² and R³ are, independently of one another, C₁ -C₄-alkyl, as well as the physiologically tolerated salts thereof.

The compounds according to the invention can be prepared, for example,as shown the following reaction schemes A and B: ##STR7##

2,6-Dimethylphenol is alkylated in a conventional manner with ahaloalkylamine, after which a Friedel-Crafts reaction with an acidchloride X--Y--COCl results in the hydroxy phenone. If Y is the group--CH═CH--, catalytic hydrogenation under conventional conditions resultsin the propiophenones. ##STR8##

2,6-Dimethylphenol is esterified with acetic anhydride in a conventionalmanner. The phenol acylation is effected by Fries rearrangement in anAlCl₃ melt. The condensation with an aldehyde X--CHO is carried outunder basic conditions, conventionally with NaOH. The last two reactionsteps can also be carried out in the reverse sequence. Subsequenthydrogenation similar to scheme A results in the propiophenone.

If necessary, the propiophenone derivatives obtained in this way areconverted into the addition salt of a physiologically tolerated acid. Acompilation of conventional physiologically tolerated acids can be foundin Fortschritte der Arzneimittelforschung (Advances in Drug Research)1966, Birkhauser Verlag, vol. 10, pages 244 to 285, Germany,Switzerland.

As a rule, the acid addition salts are obtained in a conventional mannerby mixing the free base or solutions thereof with the appropriate acidor solutions thereof in an organic solvent, for example a lower alcoholsuch as methanol, ethanol or propanol, or a lower ketone such asacetone, methyl ethyl ketone or methyl isobutyl ketone, or an ether suchas diethyl ether, tetrahydrofuran or dioxane. Mixtures of the saidsolvents can be used to improve crystallization. In addition,pharmaceutically acceptable aqueous solutions of acid addition compoundsof the p-hydroxy phenone derivatives of the formula I can be prepared bydissolving the free bases in an aqueous solution of the acid.

The present invention also relates to therapeutic agents for topicaland, especially, systemic administration, which contain a compound ofthe formula I, besides conventional carriers and/or other pharmaceuticalaids, as active substance, and to the use of a compound of the formula Ifor the preparation of a drug, in particular of an antiarrhythmic.

The novel compounds have, as is shown by the following experimentalresults, a good class III antiarrhythmic action:

The experimental animals are male and female Pirbright white guinea-pigsweighing from 300 to 500 g. They are anesthetized with 1.5 g/kg urethanei.p. The substances are administered intravenously. The ECG conductiontimes and the heart rate are measured from a recording from extremitylead II. The measured variables are the QT and PQ intervals and theheart rate. 4 to 6 animals are used per dose. The criterion of a classIII action is an increase in the QT interval compared with the valuesbefore administration of the substance. An increase in PQ and a largedecrease in the heart rate serve as exclusion criteria. The ED 20% iscalculated from the linear relation between log dose (mg/kg) of thesubstance and the relative increase in the QT interval (in %).

                  TABLE 1                                                         ______________________________________                                        Class III antiarrhythmic action in guinea-pigs                                after intravenous administration.                                                        Increase in the QT interval                                        Example    ED 20%              [mg/kg]                                        ______________________________________                                        2                        1.1                                                  4                        1.2                                                  5                        1.0                                                  D-Sotalol                3.6                                                  ______________________________________                                    

The novel substances are therefore suitable for the treatment ofarrhythmias otherwise resistant to therapy, in particular they eliminateventricular tachycardias occurring after myocardial infarct and based ona reentry mechanism (Lit. Cardiac Arrhythmia, Ed. P. Brugada, H. J. J.Wellens, Futura Publishing Co., Mount Kisko, N. Y. 1987).

The therapeutic agents or compositions are prepared by mixing the activesubstance with the conventional liquid or solid carriers or diluents andthe aids conventionally used in pharmaceutical technology, in accordancewith the desired mode of administration and with the dosage suitable forthe application.

The agents can be administered orally, parenterally or topically.Examples of compositions of this nature are tablets, film-coatedtablets, sugar-coated tablets, capsules, pills, powders, solutions orsuspensions, infusion or injection solutions as well as pastes,ointments, gels, creams, lotions, dusting powders, solutions oremulsions and sprays.

The therapeutic agents can contain the compounds to be used according tothe invention in a concentration of from 0.0001 to 1%, preferably 0.001to 0.1%, for local application and preferably in a single dose of from10 to 500 mg for systemic administration and can be administered in oneor more doses each day, depending on the nature and severity of thedisease.

Examples of aids conventionally used in pharmaceutical technology are,for local application, alcohols such as ethanol, isopropanol,ethoxylated castor oil or ethoxylated hydrogenated castor oil,polyacrylic acid, glycerol monostearate, liquid paraffin, petrolatum,lanolin, polyethylene glycol, polypropylene glycol, stearate andethoxylated fatty alcohol and, for systemic administration, lactose,propylene glycol and ethanol, starch, talc and polyvinylpyrrolidone. Itis also possible to add to the products an antioxidant, for exampletocopherol and butylated hydroxyanisole or butylated hydroxytoluene, oradditives to improve the flavor, stabilizers, emulsifiers, bleachingagents etc. It is requisite that all the substances used in thepreparation of pharmaceutical compositions are toxicologically innocuousand compatible with the active substances used.

EXAMPLE 1 4Chloro-3', 5'-dimethyl-4'-[2-(N-pyrrolidinyl)ethoxy]-chalconesemifumarate.

46.7 g (0.38 mole) of 2,6-dimethylphenol, 65.0 g (0.38 mole) ofN-(2-chloroethyl)pyrrolidine hydrochloride, 210.1 g (1.52 mole) ofpotassium carbonate and 2 g of NaI in 300 ml of ethyl methyl ketone wererefluxed for 48 h. The reaction mixture was concentrated under reducedpressure, the residue was partitioned between water and ether, theorganic phase was separated off, washed with water and dried, and excessethereal hydrogen chloride solution was added. The precipitated productwas recrystallized from 10/1 ethyl acetate/isopropanol. 63 g ofN-[2-(2,6-dimethylphenoxy)ethyl]pyrrolidine hydrochloride were obtained.

To 10.0 g (40 mmole) of the above product dissolved in 50 ml ofmethylene chloride were added 10.1 g (50 mmol) of E-4-chlorocinnamoylchloride dissolved in methylene chloride, and subsequent 10.7 g (80mmole) of anhydrous aluminum chloride in portions. The reaction mixturewas refluxed for 1 h and then poured into ice/hydrochloric acid, themixture was made alkaline with dilute sodium hydroxide solution, and theorganic phase was separated off, washed with water, dried andconcentrated under reduced pressure. The residue was dissolved in hoti-propanol, and an equimolar amount of fumaric acid dissolved in boilingi-propanol was added. The mixture was concentrated and the residue wasrecrystallized from ethanol/H₂ O.

4.9 g of the product were obtained. Melting 215-217° C.

EXAMPLE 2 3,5-Dimethyl-4-[2-(1-pyrrolidinyl)ethoxy]phenylE-2-(1-methyl-2-pyrrolyl)ethenyl ketone fumarate

100 g (0.82 mole) of 2,6-dimethylphenol and 167.4 g (1.64 mole) ofacetic anhydride were refluxed for 4 h. The reaction mixture was pouredonto ice and extracted with methylene chloride. The organic phase waswashed with dilute sodium hydroxide solution, dried and concentratedunder reduced pressure. 138 g of 2,6-dimethylphenyl acetate wereobtained. To this product were added 120.2 g (0.9 mole) of anhydrousaluminum chloride in portions, during which the temperature rose to 85°C. The mixture was then heated at 110° C. for 30 min and left to cool.The viscous paste was poured onto ice/hydrochloric acid, and theprecipitated product was filtered off. Recrystallization from 1/1methanol/water resulted in 103.6 g of3,5-dimethyl-4-hydroxyacetophenone.

39.8 g (0.24 mole) of the above product, 32.6 g ofN-(2-chloroethyl)pyrrolidine, 66.3 g (0.48 mole) of potassium carbonateand 0.5 g of cryptand-[2.2.2] in 300 ml of acetonitrile were refluxedfor 2 h. The carbonate was filtered off, and the filtrate wasconcentrated under reduced pressure. The residue was partitioned betweenmethylene chloride and dilute sodium hydroxide solution, and the organicphase was washed with water, dried and concentrated under reducedpressure. 40.5 g of3-5-dimethyl-4-(2-(1-pyrrolidinyl)ethoxy)acetophenone were obtained as acrude product which was immediately processed further.

5.2 g (20 mmol) of the above product and 4.4 g (40 mmol) of1-methyl-2-pyrrolecarbaldehyde were dissolved in 100 ml of methanol, 8 gof 50% strength sodium hydroxide solution were added, and the mixturewas refluxed for 1 h. The reaction mixture was concentrated underreduced pressure, the residue was partitioned between water andmethylene chloride, and the organic phase was dried and concentratedunder reduced pressure. The residue was taken up a little hotisopropanol, and an equimolar amount of fumaric acid dissolved inisopropanol was added. The solution was left to crystallize, resultingin 7.5 g of the target product. Melting point 198°-201° C.

The following were prepared in a similar manner to Example 2

b 3. 3,5-Dimethyl-4-[2-(1-pyrrolidinyl)ethoxy]phenylE-2-[1-(i-propyl)-4-pyrazolyl]ethenyl ketone dihydrochloride.

4. 3,5-Dimethyl-4-[2-(1-pyrrolidinyl)ethoxy]phenylE-2-(3-methyl-2-thienyl)ethenyl ketone fumarate. Melting point 167°-169°C.

5.3',5'-Dimethyl-4'-[2-(1-pyrrolidinyl)ethoxy]-2-trifluoromethylchalconefumarate. Melting point 171°-174° C.

6. 2-Chloro-3',5'-dimethyl-4'-[2-(1-pyrrolidinyl)-ethoxy]chalconehydrochloride. Melting point 181°-184° C.

7. 3,5-Dimethyl-4-[2-(1-pyrrolidinyl)ethoxy]phenylE-2-(1-indolyl)ethenyl ketone fumarate. Melting point 217-219° C.

The following was prepared from the compound of Example 5 byhydrogenation similar to Example 1:

8.3,5-Dimethyl-4-[2-(1-pyrrolidinyl)ethoxy]-3'-(2-trifluoromethylphenyl)propiophenonefumarate. Melting point 151° C.

We claim:
 1. A p-hydroxy phenone derivative of the Formula I ##STR9##where X is Δ a heteroaryl of the structure: ##STR10## with R² =C₁ -C₄-alkyl,Y is a bridging member of the formula --CH═CH--, --CH₂ CH₂ -- orCH₂ --, n is on of the number 2, 3 or 4 and Z is an amino group of theformula --NR² R³ or N-prrolidyl or N-piperidyl, where R² and R³ are,independently of one another, C₁ -C₄ -alkyl, as well as thephysiologically tolerated salts thereof.
 2. A drug for topicaladministration, which contains as active substance from 0.001 to 1% byweight of a p-hydroxy phenone derivative as claimed in claim 1, inaddition to conventional aids.
 3. A drug for systemic administration,which contains from 10 to 500 mg of a p-hydroxy phenone derivative asclaimed in claim 1 per single dose, in addition to conventional aids. 4.An antiarrhythmic of Vaughan-Williams class III, which contains aneffective amount of a p-hydroxy phenone derivative as claimed in claim1, in additional to conventional aids.